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Intranasal delivery of therapeutic enzymes to the central nervous system for the treatment of lysosomal storage diseases

a technology of lysosomal storage and therapeutic enzymes, which is applied in the direction of peptide/protein ingredients, drug compositions, enzymology, etc., can solve the problems of relatively large inability to facilitate or achieve delivery, and achieve the effect of maximizing the amount of enzymes reaching the brain

Active Publication Date: 2013-12-17
RGT UNIV OF MINNESOTA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about a nasal spray device that can deliver a lysosomal storage enzyme to the brain through the nasal cavity. The device sprays only when the connection between the nose and lungs is closed, preventing delivery to the lungs. The device can be a pressurized olfactory delivery device or a metered dose nasal spray device, and it delivers the enzyme high in the nasal cavity to reach the olfactory epithelium and the respiratory epithelium for maximum absorption by the brain.

Problems solved by technology

Further, it was unexpected that the enzyme reached the brain in relatively large amounts.
In one embodiment, delivery is not facilitated or accomplished using iontophoresis.

Method used

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  • Intranasal delivery of therapeutic enzymes to the central nervous system for the treatment of lysosomal storage diseases
  • Intranasal delivery of therapeutic enzymes to the central nervous system for the treatment of lysosomal storage diseases
  • Intranasal delivery of therapeutic enzymes to the central nervous system for the treatment of lysosomal storage diseases

Examples

Experimental program
Comparison scheme
Effect test

example i

Intranasal Administration of IDUA Leads to Widespread Distribution in the Brains of Mice

[0076]IDUA− / − mice were anesthetized and treated with either 24 μL of PBS vehicle or laronidase (Aldurazyme) that had been concentrated by centrifugation in an Amicon Centriplus YM-10 column to a final concentration of about 1.5 mg / mL. Prior to concentration, the laronidase was diluted with two parts Elliots B solution (which is comparable in pH, electrolyte composition, glucose content, and osmolarity to cerebrospinal fluid, and includes sodium chloride, sodium bicarbonate, dextrose, magnesium sulfate, potassium chloride, calcium chloride, and sodium phosphate, resulting in sodium 149 mEq / liter, potassium 4.0 mEq / liter, calcium 2.7 mEq / liter, magnesium 2.4 mEq / liter, bicarbonate 22.6 mEq / liter, chloride 132 mEq / liter, sulfate 2.4 mEq / liter, and phosphate 1.5 mEq / liter). The treatments were administered by applying a series of eight 3 μL drops to the nasal cavity of each mouse at one-minute inter...

example ii

Testing the Effectiveness of Enzyme Delivery to the CNS

[0078]The effectiveness of enzyme delivery to the CNS is described in the following examples, in which iduronidase enzyme was expressed in all sections of the brain after delivery of adeno-associated virus vector encoding human IDUA.

[0079]An AAV 2 based vector (AAV2-MCI) was constructed to contain the human IDUA (hIDUA) coding sequence under regulation of a strong mini-CAGS promoter (Ohlfest et al., 2005) (FIG. 2A). This vector was packaged at the University of Florida Vector Core using AAV 8 capsid protein, and 2×1010 vector genomes was stereotactically infused into the right lateral ventricle of neonatal (4-6 day old) IDUA-deficient mice, anticipating that this route of administration would provide widespread distribution and vector-mediated hIDUA expression throughout the brain.

[0080]The animals were sacrificed at 10 months of age, and brain tissue was harvested by microdissection and homogenized. IDUA was undetectable in bra...

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Abstract

The invention provides a method to prevent, inhibit or treat one or more neurological symptoms associated with a lysosomal storage disease in a mammal in need thereof, which includes intranasally administering to the mammal a composition comprising an effective amount of a lysosomal storage enzyme or a recombinant adeno-associated virus vector comprising an open reading frame encoding a lysosomal storage enzyme. Also provided are compositions and devices useful in the methods.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of the filing date of U.S. application Ser. No. 61 / 484,378, filed on May 10, 2011, the disclosure of which is incorporated by reference herein.BACKGROUND[0002]The mucopolysaccharidoses (MPSs) are a group of 11 storage diseases caused by disruptions in glycosaminoglycan (GAG) catabolism, leading to their accumulation in lysosomes (Muenzer, 2004; Munoz-Rojas et al., 2008). Manifestations of varying severity include organomegaly, skeletal dysplasias, cardiac and pulmonary obstruction and neurological deterioration. For MPS I, deficiency of iduronidase (IDUA), severity ranges from mild (Scheie syndrome) to moderate (Hurler-Scheie) to severe (Hurler syndrome), with the latter resulting in neurologic deficiency and death by age 15 (Muenzer, 2004; Munoz-Rojas et al., 2008). Therapies for MPSs have been for the most part palliative. However, there are some of the MPS diseases, including Hurler syndrome, for whi...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K38/46
CPCA61K38/46A61K38/47C12N9/18A61K9/0043C12Y302/01076C12N9/2402A61K38/465C12Y302/01022C12Y302/01023C12Y302/01031C12Y302/01045C12Y302/0105C12Y302/01052C12Y301/06013C12N15/86A61P25/00
Inventor WOLF, DANIEL A.FREY, II, WILLIAM H.MCIVOR, R. SCOTTHANSON, LEAH R.
Owner RGT UNIV OF MINNESOTA
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